Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes
View Patent ↗The present invention provides novel pyrazoles that are useful as cannabinoid receptor antagonists and pharmaceutical compositions thereof and methods of using the same for treating obesity, diabetes, hepatic disorders, and/or cardiometabolic disorders.
1. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is insulin resistance:
wherein:
X, Y, X′, Y′, X″, and Y″ are independently selected from: H, C 1-6 alkyl, halogen, CF 3 , O—C 1-6 alkyl, NO 2 , NR 2 , O(CH 2 ) n CO 2 R, O(CH 2 ) n CN, OCH 2 CH═CHCO 2 R, CH 2 O(CH 2 ) n CO 2 R, CH 2 OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , CH 2 O(CH 2 ) n PO(OR) 2 , NR a (CH 2 ) n CO 2 R, NR a (CH 2 ) n PO(OR) 2 , NR a CH 2 CH═CHCO 2 R, NR a SO 2 R, NR a CO(CH 2 ) n CO 2 R, NR a CO(CH 2 ) n CONR a 2 , O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, CH 2 O(CH 2 ) n C 6 H 4 CO 2 R, O(CH 2 ) n C 6 H 4 CONR a 2 , O(CH 2 ) n C 6 H 4 (CH 2 ) n CONR a 2 , O(CH 2 ) n C 6 H 4 -tetrazole, CH 2 O(CH 2 ) n C 6 H 4 CONR a 2 , CH 2 O(CH 2 ) n C 6 H 4 -tetrazole, O(CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, NR a (CH 2 ) n C 6 H 4 CO 2 R, CH 2 NR a (CH 2 ) n C 6 H 4 CO 2 R, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CO 2 R, NR a (CH 2 ) n C 6 H 4 CONR a 2 , CH 2 NR a (CH 2 ) n C 6 H 4 CONR a 2 , NR a (CH 2 ) n C 6 H 4 (CH 2 ) n CONR a 2 , NR a (CH 2 ) n C 6 H 4 -tetrazole, CH 2 NR a (CH 2 ) n C 6 H 4 -tetrazole, NR a (CH 2 ) n C 6 H 4 (CH 2 ) n -tetrazole, CONHOH, C(NH)NR a 2 , (CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n CONR a 2 , O(CH 2 ) n C(NH)NR a 2 , O(CH 2 ) n C(NOH)NR a 2 , CH 2 O(CH 2 ) n CONR a 2 , NR a (CH 2 ) n CONR a 2 , OCH 2 CH═CHCONR a 2 , CH 2 OCH 2 CH═CHCONR a 2 , NR a CH 2 CH═CHCONR a 2 , (CH 2 ) m -tetrazole, O(CH 2 ) n -tetrazole, O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and SO 2 NHCH 3 ;
Z is selected from: H, C 1-6 alkyl, OH, O—C 1-6 alkyl, O(CH 2 CH 2 O) p R, OC(O)—C 1-6 alkyl, O(CH 2 ) n CO 2 R, OCH 2 CH═CHCO 2 R, O(CH 2 ) n PO(OR) 2 , O(CH 2 ) n CONR a 2 , O(CH 2 ) n C(NH)NH 2 , O(CH 2 ) n C(NOH)NR a 2 , OCH 2 CH═CHCONR a 2 , O(CH 2 ) n -phenyl-(CH 2 ) m CO 2 R, and O(CH 2 ) n -phenyl-(CH 2 ) m -tetrazole;
Z′ is selected from H, CO 2 R, and CONR a 2 ;
Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 3 R, (CH 2 ) m CHA(CH 2 ) m C(NH)NH 2 , (CH 2 ) m CHA(CH 2 ) m C(NOH)NH 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;
provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
A is selected from H, C 1-6 alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b 2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4 alkyl, halogen, CF 3 , O—C 1-4 alkyl, and NO 2 ;
alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and (a) A is selected from OH, (CH 2 ) n CO 2 R b , and (CH 2 ) n C(O)NR b 2 ; (b) R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ; or (c) both (a) and (b);
A″ is C 1-6 alkyl;
M is C═O or SO 2 ;
R is independently selected from H, (CH 2 ) m (CHR b ) n (CH 2 ) m OH, CH(CH 2 OH) 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R a is independently selected from H, (CH 2 ) m (CHR) n (CH 2 ) m OH, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
m is selected from 0, 1, 2, 3, and 4; and,
n is selected from 1, 2, 3, and 4.
2. The method of claim 1 , wherein: M is SO 2 .
3. The method of claim 1 , wherein the compound is of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof:
4. The method of claim 1 , wherein the compound is of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof:
5. The method of claim 1 , wherein the compound is of formula Ic or a stereoisomer or pharmaceutically acceptable salt thereof:
6. The method of claim 1 , wherein the compound is a compound of formula Ia or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C 1-4 alkyl, halogen, CF 3 , O—C 1-4 alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ;
Z is selected from: H, C 1-4 alkyl, OH, O—C 1-4 alkyl, acetyloxy, and propionyloxy;
Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;
provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
A is selected from H, C 1-4 alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b 2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4 alkyl, halogen, CF 3 , O—C 1-4 alkyl, and NO 2 ;
alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;
R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
p is selected from 2, 3, 4, 5, 6, 7, and 8;
m is independently selected from 0, 1, 2, and 3; and,
n is independently selected from 1, 2, and 3.
7. The method of claim 6 , wherein:
Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;
provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
alternatively, Q is CHA(CH 2 ) m C(O)NR 2 and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;
M is SO 2 ;
R is independently selected from H and C 1-4 alkyl;
R b is independently selected from H and C 1-4 alkyl;
m is independently selected from 0, 1, and 2; and,
n is independently selected from 1 and 2.
8. The method of claim 1 , wherein the compound is a compound of formula Ib or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
X, Y, X′, Y′, X″, and Y″ are individually selected from the following: H, C 1-4 alkyl, halogen, CF 3 , O—C 1-4 alkyl, NO 2 , O(CH 2 CH 2 O) p R, NR a (CH 2 CH 2 O) p R, and NR 2 ;
Z is selected from: H, C 1-4 alkyl, OH, O—C 1-4 alkyl, acetyloxy, and propionyloxy;
Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) n CHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CO 2 R, (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , C 3 -C 6 -cycloalkylene-(CH 2 ) m CO 2 R, and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;
provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 or (CH 2 ) m CAA″(CH 2 ) m CO 2 R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
A is selected from H, C 1-4 alkyl, (CH 2 ) m C 3-6 -cycloalkyl, OH, CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH, (CH 2 ) n CO 2 R b , (CH 2 ) n C(O)NR b 2 , and (CH 2 ) m -phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C 1-4 alkyl, halogen, CF 3 , O—C 1-4 alkyl, and NO 2 ;
alternatively, Q is CHA(CH 2 ) m C(O)NR 2 or CHA(CH 2 ) m CO 2 R, and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;
R is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R b is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
p is selected from 2, 3, 4, 5, 6, 7, and 8;
m is independently selected from 0, 1, 2, and 3; and,
n is independently selected from 1, 2, and 3.
9. The method of claim 8 , wherein:
Q is selected from: (CH 2 ) n CHA(CH 2 ) m C(O)NR 2 , (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 , (CH 2 ) m CHA(CH 2 ) m SO 2 NR 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CAA″(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , (CH 2 ) m CHA(CH 2 ) m CONHCHA(CH 2 ) m CONHCHA(CH 2 ) m CONR a 2 , C 3 -C 6 -cyclic amino-(CH 2 ) m CO 2 R, C 3 -C 6 -cyclic amino-(CH 2 ) m CONR a 2 , and C 3 -C 6 -cycloalkylene-(CH 2 ) m CONR a 2 ;
provided that when Q is (CH 2 ) m CAA″(CH 2 ) m C(O)NR 2 then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
alternatively, Q is CHA(CH 2 ) m C(O)NR 2 and A is OH or (CH 2 ) n CO 2 R b or R is (CH 2 ) m (CHR b ) n (CH 2 ) m OH or CH(CH 2 OH) 2 ;
M is SO 2 ;
R is independently selected from H and C 1-4 alkyl;
R b is independently selected from H and C 1-4 alkyl;
m is independently selected from 0, 1, and 2; and,
n is independently selected from 1 and 2.
10. The method of claim 1 , wherein the compound is selected from Table B or a stereoisomer or a pharmaceutically acceptable salt thereof:
TABLE B
Number
Q
Y″
X″
X
1
CH 2 CH 2 CH(OH)CO 2 Me
4-Cl
H
Cl
2
CH(CH 2 CO 2 tBu)CO 2 Me
4-Cl
H
Cl
3
C(CH 3 ) 2 CO 2 H
4-Cl
H
Cl
4
C(CH 3 ) 2 CONH—
4-Cl
H
Cl
CH(CH 3 )CO 2 Me
5
CH(CH(CH 3 ) 2 )—
4-OMe
H
Cl
CONHCH 2 CH 2 OH
6
CH 2 CH(OH)CH 2 CONH 2
4-Cl
H
Cl
7
CHCH(CH 3 ) 2 CONH—
4-Cl
H
Cl
CH(CH 2 OH) 2
8
CH 2 CH 2 CH(OH)CONH 2
4-Cl
H
Cl
9
CHCH(CH 3 ) 2 CONH—
4-OMe
H
Cl
CH(CH 2 OH) 2
10
CH(CH 2 CONH 2 )CONH 2
4-Cl
H
Cl
11
CH 2 CONHCH 2 CONH 2
4-Cl
H
Cl
12
CH 2 CONHCH 2 CONH 2
4-OMe
H
Cl
13
CH 2 CONH—
4-OMe
H
Cl
CH(CHCH 3 OH)CONH 2
14
CHCH 3 CONH—CH 2 CONH 2
4-Cl
H
Cl
15
CHCH 3 CONH—CH 2 CONH 2
4-OMe
H
Cl
16
CHCH(CH 3 ) 2 CONH—
4-Cl
H
Cl
CH 2 CONH 2
17
CHCH(CH 3 ) 2 CONH—
4-Cl
H
Cl
CHCH 3 CONH 2
18
CHCH 3 CONH—
4-Cl
H
Cl
CHCH 2 OHCONH 2
19
CHCH 3 CONH—
4-Cl
H
Cl
CHCH 3 CONH 2
20
4-Cl
H
Cl
21
CH 2 CH 2 SO 2 NH 2
4-Cl
H
Cl.
11. A method of treating a disease, comprising: administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the disease is insulin resistance:
TABLE A
Number
Q
Y″
X″
X
1
CH(CH 3 )CH 2 CO 2 Et
4-Cl
H
Cl
2
CH(CH 3 )CH 2 CO 2 H
4-Cl
H
Cl
3
CH 2 CO 2 Me
4-Cl
H
Cl
4
CH 2 CO 2 H
4-Cl
H
Cl
5
CH(CH 3 )CO 2 Me
4-Cl
H
Cl
6
CH(CHOHCH 3 )CO 2 Me
4-Cl
H
Cl
7
CH(C(CH 3 ) 3 )CO 2 Me
4-Cl
H
Cl
8
CH 2 CO 2 Me
4-OMe
3-OMe
Cl
10
CH 2 CO 2 Me
4-OMe
3-Cl
Cl
11
CH(CH 2 OH)CO 2 Me
4-Cl
H
Cl
12
CH 2 CONHCH 2 CO 2 Me
4-Cl
H
Cl
13
CH(CH 3 )CONH—
4-Cl
H
Cl
CH 2 CO 2 Me
14
CH(CH(CH 3 ) 2 )CONH—
4-Cl
H
Cl
CH 2 CO 2 Me
15
CH 2 CONHCH 2 CO 2 Me
4-OMe
H
Cl
16
CH 2 CONH 2
4-Cl
H
Cl
16
CH(CH 3 )CONH 2
4-Cl
H
Cl
17
CH 2 CH 2 CONH 2
4-Cl
H
Cl
18
CH(CH 3 )CH 2 CONH 2
4-Cl
H
Cl
19
CH(C(CH 3 ) 3 CONH 2
4-Cl
H
Cl
20
CH(CH(CH 3 ) 2 )CONH 2
4-Cl
H
Cl
21
CHCH(CH 3 ) 2 )—
4-Cl
H
Cl
CONHCH 3
22
CH(CHOHCH 3 )CONH 2
4-Cl
H
Cl
23
CH 2 CONH 2
4-OMe
H
Cl
24
CH(CH 3 )CONH 2
4-OMe
H
Cl
25
CH(CH 3 )CONH 2
4-OCH 2 -
H
Cl
CN
26
C(CH 3 ) 2 CONH 2
4-Cl
H
Cl
27
CH 2 CH(CH 3 )CONH 2
4-Cl
H
Cl
28
CH(CH 3 )CONH 2
4-OMe
4-OMe
Cl
29
CH(CH 3 )CONH 2
4-OMe
3-Cl
Cl
30
CH 2 CONH 2
4-Cl
H
OMe
31
CH(CH(CH 3 ) 2 )CONH 2
3-OMe
H
Cl
32
CH 2 CH 2 CONH 2
4-Cl
H
Cl
TABLE C
Number
Q
Y″
X″
X
1
Me
4-OCH 2 CO 2 Et
H
Cl
2
Me
4-CONHOH
Cl
Cl.
12. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
22. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
23. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
25. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
26. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
27. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
28. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.
29. The method of claim 1 , wherein the compound is:
or a stereoisomer or a pharmaceutically acceptable salt thereof.